Apo-calypse now? Apolipoprotein profiling to reduce residual cardiovascular disease

Abstract

This thesis explores the use of a multiplex apolipoprotein panel, comprising nine apolipoproteins, to improve cardiovascular risk prediction beyond conventional lipid testing. As key proteins in lipid metabolism, apolipoproteins offer a biologically refined approach to assessing residual cardiovascular risk. To address this unmet clinical need, an LC-MRM-MS–based multiplex assay was evaluated, enabling simultaneous antibody-independent quantification of multiple apolipoproteins. The clinical performance of the panel was first assessed in the NEO study, a Dutch cohort of predominantly overweight adults without cardiovascular disease, where it improved cardiovascular risk prediction beyond traditional lipid measures. Reference intervals for all nine apolipoproteins were also established in a subpopulation representative of the general Dutch population. In the ODYSSEY OUTCOMES trial, the panel was evaluated in a secondary prevention setting to assess its clinical performance and effectiveness. It demonstrated additional predictive value and identified patients more likely to benefit from PCSK9 inhibitor (alirocumab) therapy. Moreover, comparison of two immunoassays with the LC-MRM-MS method for Lp(a) measurement showed that, although population-level predictions were similar, notable individual-level discrepancies were observed. Finally, the thesis discusses how integrating the apolipoprotein panel into clinical practice could advance precision diagnostics and enable more personalized cardiovascular risk management.